a) Field of the Invention
The present invention relates to a transcutaneous dosing element using iontophoresis.
b) Description of the Related Art
Transcutaneous dosing is an excellent drug delivery system for dosing a particular area of a living body with a drug at a predetermined density. Transcutaneous dosed drugs circulate with blood in a living body at a smaller percentage than venously injected or orally dosed drugs so that harmful side effects may be reduced and the amount of drug can be reduced. For these reasons, transcutaneous dosing can be utilized not only to alleviate inflammation and pain, but also to remedy some chronic diseases while patients may be able to continue normal daily living depending on the degree of seriousness of the diseases. For example, transcutaneous dosing may be applied for treatment of chronic diseases of muscular and osteal systems, for prevention of heart attack, for alleviation of bronchitis, and for treatment of nervous system disease.
For general transcutaneous dosing, a plaster coated with a matrix (meaning not a lattice shape of circuit devices, but base material containing effective drug components) is put in contact with a particular skin area to permeate a drug through subcutaneous tissues at a predetermined density, by means of concentration diffusion. Transcutaneous drugs effective for medical treatment are generally made of high polymer compounds and have a complicated three-dimensional structure. Therefore, use of simple concentration diffusion phenomenon may often result in insufficient treatment effects because drugs with a necessary concentration do not reach an affected part. The skin of a human body has a complicated multi-layer structure and a function of preventing foreign particles from being externally permeated. It is therefore not easy for high polymer drugs to permeate through subcutaneous tissues by overcoming the skin barrier.
As techniques for improving an effective permeation of transcutaneous dosing, use of iontophoresis and recently use of a polymer drug mixed with an absorption accelerator have drawn attention.
With the former techniques, effective components of a drug are ionized. An external electric power is applied between two electrodes (active and counter electrodes) mounted on skin to form an electric path via the skin, with one of the electrodes the, active electrode, being coated with effective components of the ionic drug, so that these components are forcibly migrated through the electric path in the skin by electric repulsion force. With the latter techniques, and, substance such as limonene, which can weaken the molecular bonding force of sebum and make the drug easy to permeate through the stratum corneum, is mixed with the drug in the matrix.
Although some of these techniques are practically used, they are still in the midst of development. Namely, the former techniques is associated with a problem of an external power source, and the latter techniques is associated with medical inefficacy.
As an external power source of iontophoresis, a fixed d.c. power source of about 100 V is used under the supervision of doctors in a hospital or the like, because the skin electric path is highly resistant (10 to 100 M.OMEGA./cm). However, since patients cannot continue normal daily living with the fixed power source, a portable compact power source (battery) is generally used. After the battery is used for some period of time, its electromotive force lowers suddenly. The effects of drug permeation by cataphoresis may lower correspondingly, or if the skin resistance lowers greatly because of a change in the conditions of skin-contact surface or perspiration, large current will flow and the skin surface may be damaged.
As a means for solving such problems, another iontophoreses has been proposed (Japanese Patent Laid-open Publication No. 60-203270) in which two metals having different ionization tendencies are ohmically-contacted at an outer side of skin to generate an electromotive force by using an electrically closed circuit formed when the metals are put in contact with skin, and ionic drug made of metallic salt of the same type as a metal forming the positive pole of a cell is coated on the skin-contact surface of an electrode forming the positive pole of the cell. As opposed to the conventional technique using an external power source (battery), this approach uses the internal reaction of a cell (oxidation-reduction reaction between electrodes). This method is also associated, however, with the following problem. When an electrically closed circuit is formed via skin, electrons start to flow from the electrode forming the negative pole of the cell (negative electrode) having a larger ionization tendency toward the electrode forming the positive pole (positive electrode), and the negative electrode from which electrons moved outside (oxidized) becomes chemically active. Since the negative electrode is surrounded with water molecules, it is obvious that before negative ions are pulled from the living skin, the following reaction occurs: EQU Me.sup.2+ +2OH.sup.- .fwdarw.Me(OH).sub.2 .fwdarw.MeO+H.sub.2 O
where Me.sup.2+ is ion of the metal constituting the negative electrode. The cell electromotive force therefore changes greatly. For example, if a magnesium alloy is used for the negative electrode, which is recommended in Japanese Patent Laid-open Publication No. 60-203270, the surface of the negative electrode is coated with MgO in a short time. Since Mg(OH).sub.2 and MgO are insulating materials, the electromotive force lowers quickly and iontophoresis stops eventually.
In order to solve this problem, the present inventor has proposed a skin-contact power generation type iontophoresis power source using a combination of a semiconductor electrode forming the negative pole of a cell and a metal electrode forming the positive pole of the cell (Japanese Patent Laid-open Publication No. Hei 3-16573), which is herein incorporated by reference. This power source as well as an ionic drug coated on the positive electrode are put in contact with skin to form an electrically closed circuit. As electrons start to flow from the semiconductor negative electrode to the metal positive electrode, holes generated at the semiconductor negative electrode drift toward the skin-contact surface, while being self-biased by an internal electric field of the Schottky barrier formed at the skin-contact surface, and permeate through the skin in the form of free holes or semiconductor ions. Therefore, the semiconductor negative electrode maintains electrical neutrality and becomes durable and stable for long term use.
This power source automatically stops generation of electric power when the electrodes are short-circuited on the skin-contact surface by perspiration or the like. Skin can therefore be protected safely, inlike as in the case of external power source.
For transcutaneous dosing by iontophoresis, it is preferable if a transcutaneous dosing element has a size and shape suitable for an affected part. It is also preferable if a transcutaneous dosing element is disposable so as to allow a patient to receive continuous dosing while continuing normal daily living.
The skin-contact power generation type iontophoresis element using the semiconductor negative electrode is, however, difficult for a patient to change the shape thereof or cut into small area elements, because the conductive matrix with the ionic drug is disposed under the metal positive electrode which is electrically connected via a wire to the semiconductor negative electrode at the remote position.
If a high polymer drug is permeated through skin by iontophoresis, a permeation density often becomes insufficient even if a power source voltage is raised or current is increased. In such a case, it is effective to physiologically activate skin cells and raise the dosing efficacy.